Biology subjects

Jurynec, M.

Publications and source records attributed to Jurynec, M..

3 recordsLinked to original sources

bioRxiv2024

Tenascin C Deletion Impairs Tendon Healing and Functional Recovery After Rotator Cuff Repair

The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR), Tenascin C null (Tnc--RCR) and Tnc heterozygous (Tnc+/--RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR, Tnc--RCR, Tnc+/--RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR, Tnc- and Tnc+/- mice had severe bone and tendon defects following rotator cuff repair. Tnc--RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss of Tnc following RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways. Tnc- mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations of Tnc, the interactions of Tnc and sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.

genetics↗

bioRxiv2022

The NOD/RIPK2 signaling pathway contributes to osteoarthritis susceptibility

Introductory paragraphOsteoarthritis (OA) is a debilitating disease characterized by loss of homeostasis of the joint with consequent remodeling of tissue architecture1. The molecular pathways that limit disease onset or progression are unknown2-5, and consequently no disease-modifying drugs are available1,6-9. We sought genes that contribute to dominant forms of hereditary OA with the aim of identifying pathways whose activity level contributes to OA susceptibility. We found seven independent alleles affecting the NOD/RIPK2 pathway. To determine if altered signaling is sufficient to confer heightened OA susceptibility, mice carrying the OA-associated hyperactive Ripk2104Asp allele were generated. Knees of heterozygous Ripk2104Asp mice exhibit no overt signs of joint remodeling. Nevertheless, the mice respond to injury with markedly advanced post-traumatic OA. Uninjured heterozygous Ripk2104Asp mice appear primed to develop OA: their knees exhibit elevated NOD/RIPK2 pathway activity, localized inflammation, and altered expression of extracellular matrix genes linked to OA. In contrast to the joint, the mice display no evidence of systemic elevated inflammation. Elevated NOD/RIPK2 signaling confers vulnerability to OA.

genetics↗

bioRxiv2020

A role for the MEGF6 gene in predisposition to osteoporosis

Osteoporosis is a common skeletal disorder characterized by deterioration of bone tissue in later life. The set of genetic factors contributing to osteoporosis is not completely specified. High-risk osteoporosis pedigrees were analyzed to identify genes that may confer susceptibility to disease. Candidate predisposition variants were identified initially by whole exome sequencing of affected-relative-pairs, approximately cousins, from ten pedigrees. Variants were filtered on the basis of population frequency, concordance between pairs of cousins, affecting a gene associated with osteoporosis, and likelihood to have functionally damaging, pathogenic consequences. Subsequently variants were tested for segregation in 68 additional relatives of the index carriers. A rare variant in MEGF6 (rs755467862) showed strong evidence of segregation with the disease phenotype. Predicted protein folding indicated the variant (Cys200Tyr) may disrupt structure of an EGF-like calcium-binding domain of MEGF6. Functional analyses demonstrated that complete loss of the paralogous genes megf6a and megf6b in zebrafish resulted in significant delay of cartilage and bone formation. Segregation analyses, in-silico protein structure modeling, and functional assays support a role for MEGF6 in predisposition to osteoporosis.

genetics↗